Anthrax Lethal and Edema Toxins Fail to Directly Impair Human Platelet Function

Abstract

Hemorrhage is a prominent clinical manifestation of systemic anthrax. Therefore, we have examined the effects of anthrax lethal and edema toxins on human platelets. We find that anthrax lethal toxin fails to cleave its target, mitogen-activated protein kinase 1, and anthrax edema toxin fails to increase intracellular cyclic adenosine monophosphate. Surface expression of toxin receptors tumor endothelial marker 8 and capillary morphogenesis gene 2, as well as coreceptor low density lipoprotein receptor-related protein 6 (LRP6), are markedly reduced, preventing toxin binding to platelets. Our studies suggest that the hemorrhagic clinical manifestations of systemic anthrax are unlikely to be caused by the direct binding and entry of anthrax toxins into human platelets.

Bacillus anthracis Cell Wall Peptidoglycan but Not Lethal or Edema Toxins Produces Changes Consistent With Disseminated Intravascular Coagulation in a Rat Model

“…Each has also been shown in vitro to impair platelet aggregation or binding in mouse or rabbit cells [35,36]. However, human platelet counts were not altered by LT or ET and displayed limited expression of the tumor endothelial marker 8 and capillary morphogenesis gene 2 receptors necessary for PA binding [37]. However, LT challenge in mice in a study different from the one noted above did produce changes in the Figure 6.…”

Frontline Science: Anthrax lethal toxin-induced, NLRP1-mediated IL-1β release is a neutrophil and PAD4-dependent event

“…We hypothesized that the 1A8 antibody binding and removal of neutrophils could induce conditions that alter platelet levels or their ability to respond to LT. Previous conflicting reports exist on LT effects on platelets 44–46 . We first tested whether the PA receptor is expressed on platelets and if LF can enter platelets.…”

Suppressive Effects of Anthrax Lethal Toxin on Megakaryopoiesis

“…In this study, we found that LT does not elicit a significant elevation of plasma D-dimer (48, 72, and 96 hours post LT treatments, unpublished results), which indicates that coagulopathy is likely not involved. Anthrax LT might impair platelet functions indirectly [15], whereas hypoxic conditions can alter platelet surface protein expression and induce procoagulant behavior [43]. Therefore, LT-induced platelet count reduction may be partially mediated through a coagulopathy-independent enhancement of platelet clearance.…”

“…Therefore, to prevent LT-induced deaths, a detailed understanding of the pathogenesis is necessary. In vitro experiments indicated that LT may inhibit platelet function directly or indirectly [14], [15]. Among platelet-suppressive manifestations, thrombocytopenia commonly develops in anthrax patients and animal models [8], [14], [16].…”